This application is a 371 of PCT/JP00/03507 filed May 31, 2000.
The present invention relates to novel leucomycin derivatives effective against Gram-positive bacteria.
Macrolide antibiotics is a class of clinically important antibacterial agents that generally have low toxicity and can be orally administered. They are basically classified into 14-membered ring macrolides and 16-membered ring macrolides based on the structural atom number of the lactone ring as an aglycone. Those frequently used clinically among the 16-membered ring macrolides are leucomycin and derivatives thereof, and studies have been made so far by many research groups to improve their efficacy. The 16-membered ring macrolide antibiotics are known to give a lower blood level than the 14-membered ring macrolides (R. Okamoto et al. J. Ferment. Technol., 57, 519, 1979), and it is one of important objects to eliminate this drawback (H. A. Kirst, Journal of Antimicrobial Chemotherapy, 28, 787, 1991).
Many studies have been made to improve the blood level. Recently, the inventors of the present invention focused their researches to the neutral saccharide moiety of the leucomycin-type 16-membered ring macrolides, which is one of metabolic sites (Shomura et al., J. Pharmaceutical Society of Japan, 102, 781, 1982), and they created various leucomycin derivatives in which said moiety was converted into a neutral saccharide that was hardly metabolized. They revealed that the derivatives had desired superior pharmacokinetics in experiments using animals (K. Ajito et al., J. Antibiot., 50, 92, 1997 and K. Kurihara et al., J. Antibiot., 50, 32, 1997).
Through various studies mainly from a viewpoint of pharmacokinetics or antibacterial activity, it is known that pharmacokinetics of the leucomycin type 16-membered ring macrolides may significantly vary depending on a structural difference, i.e., whether the hydroxyl group at 3-position of the lactone ring is free or acylated, and that those having an acyl group generally give better results in blood level in vivo (Inoue, Annual Report of Meiji Seika, 13, 100, 1973).
Spiramycin (SPM) is also a 16-membered ring macrolide having 17-demetyl-17-formylplatenolide II as a basic aglycone like leucomycin. SPMs also have different stabilities in blood serum depending on a structure at 3-position, i.e., SPM I having a free 3-hydroxyl group is less stable in rat blood serum than SPM II or SPM III which has an acyl group at the 3-position. As one of rat major metabolites of SPM I, a metabolite is reported in which the 3-hydroxyl group and the aldehyde portion form a hemiacetal and thus the lactone ring is cleaved (A. Inoue et al., J. Antibiot., 36, 442, 1983).
Both of leucomycins and SPMs have a unique chemical property that the 3-hydroxyl group and the 18-aldehyde portion easily form a hemiacetal under a basic condition. Assuming that this chemical property is attributable to the fact that they have the same basic aglycone moiety, it is presumed that leucomycins having a free hydroxyl group at the 3-position have the same in vivo behavior as that of SPM I.
On the basis of the above facts, it is also presumed that a free hydroxyl group at the 3-position is disadvantageous in the leucomycin-type 16-membered ring macrolides from viewpoints of stability and metabolism, and improvements of stability and efficacy is expected by a structural conversion at that position.
As for SPM I, compounds are reported which are derived by introducing methyl group at the hydroxyl group at the 3-position of SPM I derivatives of which 3xe2x80x3- and 4xe2x80x3-positions are diacylated. However, since the publication fails to give a result of direct comparison of the SPM I derivatives as a raw material of which 3xe2x80x3- and 4xe2x80x3-positions were diacylated and the methylated derivative, contribution of the methylation of 3-hydroxyl group to the activity was identified (Omura et al., Japanese Patent Publication (Kokai) No. 61-126096).
Whilst as for 16-membered ring macrolides other than SPM, no compound is known in which hydroxyl group at the 3-position is alkylated (for example, methylated). Therefore, it is impossible to predict activity and stability of compounds with an alkylated hydroxyl group at the 3-position which is derived from the natural and non-natural leucomycin-type 16-membered ring macrolides having free hydroxyl group at the 3-position.
Further, from a viewpoint of inhibition of the aforementioned hemiacetal formation of the hydroxyl group at the 3-position and the aldehyde moiety at the 18-position, epi-type derivatives wherein the hydroxyl group at the 3-position of the natural-type compounds is inverted are expected to be effective for inhibition of the hemiacetal formation, since the inversion of the hydroxyl group at the 3-position may have a reaction site of the hydroxyl group alienate from the 18-aldehyde portion. However, no 3-epi-type derivative of the 16-membered ring macrolide is known in which the hydroxyl group at the 3-position is inverted, and therefore, activity of such compound is also unpredictable.
The present invention mainly relates to useful novel leucomycin derivatives and pharmacologically acceptable salts thereof.
The inventors of the present invention conducted various studies to solve the aforementioned problems, and synthesized novel leucomycin derivatives by using leucomycin-type 16-membered ring macrolides having a free hydroxyl group at the 3-position as starting materials and alkylating the hydroxyl group at the 3-position. At the same time, they established a method for alkylating the hydroxyl group at the 3-position regardless of a side chain structure modifying the 3xe2x80x3- and 4xe2x80x3-hydroxyl groups of the mycarose as the neutral saccharide moiety. In addition, they found that the Heck reaction (R. F. Heck, Org. Reactions, 27, 345 (1982)) progressed on the 3-O-alkenyl derivatives obtained by the above method, thereby various side chains can be introduced into the derivatives.
Furthermore, they successfully created novel 3-epi type leucomycin derivatives having a non-natural type 3-hydroxyl group by producing key intermediate compounds which were obtained by efficiently oxidizing the free hydroxyl group at the 3-position of the natural-type leucomycins.
As a result, the inventors found that the derivatives provided as the compounds of the present invention had enhanced activity and higher stability in blood plasma compared with the conventional leucomycin analogues, and on the basis of the finding, they achieved the present invention. In the leucomycin-type 16-membered ring macrolides, no compound is known that apparently has generally enhanced antibacterial activity attributable to an introduced atomic group, except for the report made by the inventors of the present invention (K. Ajito et al., J. Antibiot., 50, 366, 1997 and K. Kurihara et al., J. Antibiot., 51, 771, 1998).
The present invention thus provides compounds represented by the following general formula (I): 
[in the formula, Rxcex1 represents a C1-C10 alkyl group, a C3-C10 alkenyl group, a C7-C15 aralkyl group, a quinolinylalkyl group, a quinolinylalkenyl group, a C2-C10 alkylcarbonyl group, a C7-C15 aralkylcarbonyl group, a C4-C7 cycloalkylcarbonyl group, benzoyl group, an imidazolylcarbonyl group, a quinolinylcarbonyl group, an N-alkylaminocarbonyl group, an N,N-dialkylaminocarbonyl group, or an N-aralkylaminocarbonyl group; R1 represents hydrogen atom, a C1-C10 alkyl group, or a C2-C10 alkylcarbonyl group; and R2 represents hydrogen atom, a C1-C10 alkyl group, or a C2-C10 alkylcarbonyl group provided that a compound wherein Rxcex1 represents a C2-C10 alkylcarbonyl group and both of R1 and R2 represent a C1-C10 alkyl group] and salts thereof.
According to the second aspect of the present invention, there are provided compounds represented by the following general formula (II): 
[in the formula, Rxcex2 represents hydrogen atom, a C2-C10 alkylcarbonyl group, a C4-C7 cycloalkylcarbonyl group, a C7-C15 aralkylcarbonyl group, benzoyl group, a pyridinylcarbonyl group, an imidazolylcarbonyl group, a quinolinylcarbonyl group, an N,N-dialkylaminocarbonyl group, an N-alkylaminocarbonyl group, or an N-aralkylaminocarbonyl group; R1 represents hydrogen atom, a C1-C10 alkyl group, or a C2-C10 alkylcarbonyl group; and R2 represents hydrogen atom, a C1-C10 alkyl group, or a C2-C10 alkylcarbonyl group] and salts thereof.
According to further aspect of the present invention, there are provided compounds and salts thereof that are preferably used for the manufacture of the compounds of the aforementioned general formula (I) and salts thereof. That is, the present invention provides compounds represented by the following general formula (III): 
[in the formula, R1 represents hydrogen atom, a C1-C10 alkyl group or a C2-C10 alkylcarbonyl group, R2 represents hydrogen atom, a C1-C10 alkyl group or a C2-C10 alkylcarbonyl group, R3 represents triethylsilyl group, triisopropylsilyl group, triphenylsilyl group, tribenzylsilyl group, dimethylisopropylsilyl group, t-butyldimethylsilyl group or t-butyldiphenylsilyl group, R4 represents a C1-C5 alkyl group, and R5 represents a C1-C5 alkyl group] and salts thereof.
According to still further aspect of the present invention, there are provided compounds that are preferably used for the manufacture of the compounds of the aforementioned general formula (II) and salts thereof. That is, the present invention provides compounds represented by the following general formula (IV): 
[in the formula, R1 represents hydrogen atom, a C1-C10 alkyl group, or a C2-C10 alkylcarbonyl group, R2 represents hydrogen atom, a C1-C10 alkyl group or a C2-C10 alkylcarbonyl group, R3 represents triethylsilyl group, triisopropylsilyl group, triphenylsilyl group, tribenzylsilyl group, dimethylisopropylsilyl group, t-butyldimethylsilyl group or t-butyldiphenylsilyl group, R4 represents a C1-C5 alkyl group, and R5 represents a C1-C5 alkyl group] and salts thereof.
The present invention also provides medicaments comprising a compound represented by the aforementioned general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and medicaments comprising a compound represented by the aforementioned general formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient. These medicaments are useful for therapeutic and/or prophylactic treatment of infectious diseases, particularly therapeutic and/or prophylactic treatment of infectious diseases caused by Gram-positive bacteria. The present invention also provides antibacterial agents comprising the compounds represented by the aforementioned general formula (I) or pharmaceutically acceptable salts thereof as an active ingredient and antibacterial agents comprising the compounds represented by the aforementioned general formula (II) or pharmaceutically acceptable salts thereof as an active ingredient. These antibacterial agents are preferably used as antibacterial agents against Gram-positive bacteria.
The present invention also provides use of the compounds represented by the aforementioned general formula (I) or pharmaceutically acceptable salts thereof for the manufacture of the aforementioned medicaments, and use of the compounds represented by the aforementioned general formula (II) or pharmaceutically acceptable salts thereof for the manufacture of the aforementioned medicaments. The present invention further provides methods for therapeutic and/or prophylactic treatment of infectious diseases, which comprises the step of administering a therapeutically and/or prophylactically effective amount of a compound represented by the aforementioned general formula (I) or a pharmaceutically acceptable salt thereof to a mammal including human, and methods for therapeutic and/or prophylactic treatment of infectious diseases, which comprises the step of administering a therapeutically and/or prophylactically effective amount of a compound represented by the aforementioned general formula (II) or a pharmaceutically acceptable salt thereof to a mammal including human.
According to a further aspect of the present invention, there are provided compounds represented by the aforementioned general formula (III) or salts thereof as synthetic intermediates for the manufacture of the compounds represented by the aforementioned general formula (I) or salts thereof, and compounds represented by the aforementioned general formula (IV) or salts thereof as synthetic intermediates for the manufacture of the compounds represented by the aforementioned general formula (II) or salts thereof.
The present invention further provides use of the compounds represented by the aforementioned general formula (III) or salts thereof as synthetic intermediates for the manufacture of the compounds represented by the aforementioned general formula (I) or salts thereof, and use of the compounds represented by the aforementioned general formula (IV) or salts thereof as synthetic intermediates for the manufacture of the compounds represented by the aforementioned general formula (II) or salts thereof.